Altered Calmodulin Degradation and Signaling in Non-Neuronal Cells from Alzheimer’s Disease Patients

Esteras, Noemí; Muñoz, Úrsula; Alquézar, Carolina; Bartolomé, Fernando Benito; Bermejo‐Pareja, Félix; Martín-Requero, Ángeles

doi:10.2174/156720512800107564

Cited by 19 publications

(22 citation statements)

References 48 publications

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“…CaM-PI3Kα binding is also supported by observations of altered CaM degradation and signaling in non-neuronal cells from Alzheimer’s disease (AD) patients [32]. The increased levels of CaM synergize with serum to overactivate PI3K/Akt in AD patient cells by direct binding of CaM to p85, leading the authors to suggest that failure of CaM degradation, and thus of Ca 2+ /CaM-dependent signaling, may be important in the development of AD.…”

Section: Cam Interacts Directly With Pi3kαmentioning

confidence: 85%

Calmodulin and PI3K Signaling in KRAS Cancers

et al. 2017

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Calmodulin (CaM) uniquely promotes signaling of oncogenic K-Ras; but not N-Ras or H-Ras. How CaM interacts with K-Ras and how this stimulates cell proliferation are among the most challenging questions in KRAS-driven cancers. Earlier data pointed to formation of a ternary complex consisting of K-Ras, PI3Kα and CaM. Recent data point to phosphorylated CaM binding to the SH2 domains of the p85 subunit of PI3Kα and activating it. Modeling suggests that the high affinity interaction between the phosphorylated CaM tyrosine motif and PI3Kα, can promote full PI3Kα activation by oncogenic K-Ras. Our up-to-date review discusses CaM’s role in PI3K signaling at the membrane in KRAS-driven cancers. This is significant since it may help development of K-Ras-specific pharmacology.

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Section: Cam Interacts Directly With Pi3kαmentioning

confidence: 85%

Calmodulin and PI3K Signaling in KRAS Cancers

et al. 2017

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“…We previously reported increased CaM content in lymphoblasts from AD patients, as a consequence of impaired proteasomal degradation of the protein [19]. The higher CaM content was associated with impaired cell survival/death mechanisms [15,36].…”

Section: Discussionmentioning

confidence: 99%

“…These features were considered peripheral signs of the disease, because current evidence relates the process of neuronal apoptosis occurring in AD to the aberrant re-entry of differentiated neurons into the cell cycle [16-18]. Moreover, we detected significantly increased levels of CaM in AD lymphoblasts [19]. …”

Section: Introductionmentioning

confidence: 99%

Calmodulin levels in blood cells as a potential biomarker of Alzheimer’s disease

Esteras

Alquézar

Encarnación

et al. 2013

Alzheimers Res Ther

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IntroductionThe clinical features of Alzheimer’s disease (AD) overlap with a number of other dementias and conclusive diagnosis is only achieved at autopsy. Accurate in-life diagnosis requires finding biomarkers suitable for early diagnosis, as well as for discrimination from other types of dementia. Mounting evidence suggests that AD-dependent processes may also affect peripheral cells. We previously reported that calmodulin (CaM) signaling is impaired in AD lymphoblasts. Here, we address the issue as to whether the assessment of CaM levels in peripheral cells could serve as a diagnostic biomarker.MethodsA total of 165 subjects were enrolled in the study, including 56 AD patients, 15 patients with mild cognitive impairment, 7 with frontotemporal dementia associated with progranulin mutations, 4 with dementia with Lewy bodies, 20 patients with Parkinson’s disease, 10 with amyotrophic lateral sclerosis, 5 with progressive supranuclear palsy, and 48 cognitively normal individuals. CaM levels were then analyzed in lymphoblasts, peripheral blood mononuclear cells and plasma. Receiver operating characteristic (ROC) curve analyses were employed to evaluate the diagnostic performance of CaM content in identifying AD patients.ResultsCompared with control individuals, CaM levels were significantly increased in AD cells, but not in the other neurodegenerative disorders. CaM levels differentiated AD from control with a sensitivity of 0.89 and a specificity of 0.82 and were not dependent on disease severity or age. MCI patients also showed higher levels of the protein.ConclusionsCaM levels could be considered a peripheral biomarker for AD in its early stage and help to discriminate from other types of dementia.

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“…The Ca 2+ /calmodulin (CaM) signaling pathway was altered in AD lymphoblasts [30]. Esteras et al [30] showed that increased levels of CaM synergize with serum to overactivate PI3K/AKT in AD cells by direct binding of CaM to the regulatory α-subunit (p85) of PI3K.…”

Section: Impaired Ups Function Is Associated With Admentioning

confidence: 99%

“…Esteras et al [30] showed that increased levels of CaM synergize with serum to overactivate PI3K/AKT in AD cells by direct binding of CaM to the regulatory α-subunit (p85) of PI3K. Because CaM degradation is primarily by way of the UPS [31], the impaired UPS impedes CaM degradation and eventually the Ca 2+ /CaM-dependent signaling pathways, which may be important in the etiopathogenesis of AD [30]. …”

Section: Impaired Ups Function Is Associated With Admentioning

confidence: 99%

Failure of Ubiquitin Proteasome System: Risk for Neurodegenerative Diseases

2014

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The ubiquitin proteasome system (UPS) is the primary proteolytic quality control system in cells and has an essential function in the nervous system. UPS dysfunction has been linked to neurodegenerative conditions, including Alzheimer's, Parkinson's and Huntington's diseases. The pathology of neurodegenerative diseases is characterized by the abnormal accumulation of insoluble protein aggregates or inclusion bodies within neurons. The failure or dysregulation of the UPS prevents the degradation of misfolded/aberrant proteins, leading to deficient synaptic function that eventually affects the nervous system. In this review, we discuss the UPS and its physiological roles in the nervous system, its influence on neuronal function, and how UPS dysfunction contributes to the development of neurodegenerative diseases.

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Altered Calmodulin Degradation and Signaling in Non-Neuronal Cells from Alzheimer’s Disease Patients

Cited by 19 publications

References 48 publications

Calmodulin and PI3K Signaling in KRAS Cancers

Calmodulin and PI3K Signaling in KRAS Cancers

Calmodulin levels in blood cells as a potential biomarker of Alzheimer’s disease

Failure of Ubiquitin Proteasome System: Risk for Neurodegenerative Diseases

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